The present invention relates to methods of using anti-inflammatory macrophages in the treatment and prevention of radiation-induced tissue injury, bone marrow failure, and graft-versus-host-disease.
There is considerable interest in developing therapies that can protect patients who have been exposed to high doses of radiation for either medical purposes, such as for treatment of certain cancers and in preparation for bone marrow transplant (BMT; also known as a hematopoietic stem cell transplant), or accidental trauma, such as from a radiation accident or a terrorist attack. For example, patients receiving an allogeneic hematopoietic stem cell transplant (AlloHSCT), which is a transfusion of hematopoietic stem and progenitor cells, from donor derived bone marrow (BM), mobilized peripheral blood, cord blood or embryonic/pluripotent stem cell derived HSC, into a recipient with a malignancy such as leukemia or non-malignant disorder such as an immunodeficiency, often undergo a pre-transplant radiation-based conditioning regimen. Pre-transplant radiation treatment causes tissue damage in the recipient and increases the risk of development of graft-versus-host disease (GVHD), a condition in which donor cells recognize the recipient's organs as “foreign” and mount an immune response to attack the recipient's own tissue. GVHD is the major cause of morbidity and mortality following AlloHSCT. Because GVHD can be a life threatening complication, it is typically treated with immunosuppressants for weeks to months. The paradox is that GVHD and the current drugs used for treating GVHD, inhibit the function of the donor T cell—simultaneously abrogating anti-tumor benefits and increasing the risk of infections in the recipient. It has been shown that mesenchymal stem cells isolated from BM are effective in treating acute GVHD after allogeneic HSCT. Le Blanc et al., Lancet 371:1579-1586 (2008).
In the case of radiation-induced trauma, exposure to high levels of radiation can cause BM failure, leading to anemia, life threatening infections, and high risks of bleeding. While victims exposed to low doses of radiation may spontaneously recover their own immune systems, those victims exposed to myeloablative doses of radiation must urgently receive allogeneic HSCT. Unfortunately coordinating allogeneic HSCT takes weeks to months, while the victim is at high risk of death. If the exposure is serious enough, the victim may even be too ill to undergo allogeneic HSCT. In addition, exposure to high dose radiation can cause damage to non-BM organs, such as lungs and gastrointestinal tract, with a high rate of morbidity and mortality. Organ damage is often the primary limiting factor in delivering higher doses of radiation for treatment of cancer, as exposure of normal tissues surrounding a tumor mass to high dose radiation could cause irreversible damage. Thus, there remains an urgent need for therapies that can be rapidly implemented following systemic or localized radiation exposure to minimize the effects of radiation on the BM, effective therapies for radiation-induced organ damage, to enhance immune recovery, and to prevent development of GVHD if patient receives allogeneic HSCT.